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Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Open accessAbstract
Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions.
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“p16 is a key trigger of cellular senescence16, and its expression increases with aging in several rodent and primate tissues17–19, suggesting its potential use as a biomarker of mammalian aging.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In 30–70% of senescent cells, this SASP entails pro-inflammatory, proapoptotic and pro-fibrotic factors7,31,40,59–64, some of which can cause previously non-senescent cells to become senescent both locally and at a distance in an endocrine manner24,39,47.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [64]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“SASP factors, senescence markers and markers of other fundamental aging processes (for example, α-Klotho) can be assayed in body fluids such as urine, saliva, blood or cerebrospinal fluid7,19,48,59,61,64,132,133.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [64]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“One fundamental aging mechanism that underlies numerous age-related diseases is cellular senescence (5).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation and can spread the senescence phenotype to surrounding cells, thereby causing systemic chronic inflammation12.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [12]
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In the citing paper
“Cellular senescence is associated with cardiovascular dysfunction in humans (Tchkonia et al., 2013; Kirkland & Tchkonia, 2014), a major cause of morbidity and mortality in the elderly.”
From The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015) · cites this paper as Tchkonia et al., 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The accumulation of senescent cells contributes to tissue and organismal aging and is a well-known aging hallmark.56”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [66]
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“Thus, interventions that reduce the burden of senescent cells could ameliorate age-related disabilities and chronic diseases as a group (Tchkonia et al., 2013; Kirkland & Tchkonia, 2014).”
From The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015) · cites this paper as Tchkonia et al., 2013
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In the citing paper
“A fundamental aging mechanism that likely contributes to chronic diseases and age-related dysfunction is cellular senescence (Kirkland, 2013b,a; Tchkonia et al., 2013; Kirkland & Tchkonia, 2014).”
From The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015) · cites this paper as Tchkonia et al., 2013
The cited source says what the claim attributes to it.
In the citing paper
“as senescent cells do not divide, drug resistance would be expected to be less likely than is the case with antibiotics or cancer treatment, in which cells proliferate and so can acquire resistance”
From The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015) · cites this paper as Tchkonia et al., 2013
The cited source says what the claim attributes to it.
In the citing paper
“Senescent cells have been identified at sites of pathology in multiple diseases and disabilities or may have systemic effects that predispose to others (Tchkonia et al., 2013; Kirkland & Tchkonia, 2014).”
From The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015) · cites this paper as Tchkonia et al., 2013
In the citing paper
“Senescent cells can also initiate a deleterious positive feedback mechanism by promoting the spread of senescence to nearby cells (17–19).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [18]
In the citing paper
“senescent cells display extensive changes in gene expression, including the expression and secretion of many proinflammatory cytokines, chemokines, growth factors, and proteases; collectively these features are termed the senescence-associated secretory phenotype (SASP) (2, 7–10).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [10]
In the citing paper
“the SASP does not depend on either p53 or p16INK4a, which suggests that it is controlled by an independent branch of the senescence regulatory network (2, 10, 20, 26).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [10]
In the citing paper
“factors secreted by senescent cells may directly or indirectly promote chronic inflammation that is thought to be a major factor in many, if not all, age-related diseases (2, 9, 10).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [10]
In the citing paper
“the accumulation of senescent cells as organisms age is thought to promote aging-related phenotypes and aging-associated diseases, including cancer and neurodegeneration, in a cell-nonautonomous manner (2, 3, 10).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [10]
In the citing paper
“These inflammatory cytokines promote senescence locally in a paracrine manner30 and perhaps, at a systemic level.111”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [111]
In the citing paper
“Activation of the p38 pathway is directly involved in the loss of telomerase activity and of proliferative capacity, as well as the increased production of inflammatory cytokines similar to the senescence-associated secretory phenotype in fibroblasts”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Tchkonia et al., 2013
In the citing paper
“This is known as the senescence associated secretory phenotype or SASP and is considered to be important for remodelling of ageing tissues [41, 42].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [42]
In the citing paper
“Cellular senescence can cause chronic inflammation through the SASP and this chronic nonmicrobial (sterile) inflammation is thought to be the prime cause of many age-related disorders such as atherosclerosis, autoimmunity, cancers and dementias [42].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [42]
In the citing paper
“Cellular senescence is characterized by an irreversible cell cycle arrest, changes in gene expression, tumour suppression activation, altered chromatin, resistance to apoptosis and increased protein synthesis89.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [89]
In the citing paper
“Because of this the accumulation of senescent cells during aging is implicated as a causal factor in aging-associated inflammation and disruptions of ECM.”
From Programmed cell death in aging (2015) · cites this paper as Tchkonia et al., 2013
In the citing paper
“The composition and intensity of the SASP response can be affected by several factors including the senescence-inducing mechanism, cell type, and the amount of time passed since senescence initiation, indicating that there is no singular SASP.12–17”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [17]
In the citing paper
“There is mounting evidence that dysregulation or inappropriate activation of senescence contributes to tumour progression and malignancy.5,7,17”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [17]
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Metadata
- Authors
- Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L.
- Affiliations
- Mayo Clinic (US)
- Buck Institute for Research on Aging (US)
- Corresponding author
- Kirkland, James L.
- Venue
- Journal of Clinical Investigation
- Published
- 2013-03-01
- Volume
- 123
- Issue
- 3
- Pages
- 966-972
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3582125
- OpenAlex
- W2108887402
- Cited by
- 1,774
- References
- 111
- Citations by year
- 2026: 129 · 2025: 138 · 2024: 163 · 2023: 150 · 2022: 142 · 2021: 180 · 2020: 162 · 2019: 145 · 2018: 138 · 2017: 122 · 2016: 105 · 2015: 92 · 2014: 72 · 2013: 33
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Ellison Medical Foundation
- Noaber Foundation
- National Institutes of Health (AG041122)
- National Institute on Aging (AG041122, P01AG041122)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, senescence-associated secretory phenotype, aging, chronic inflammation, age-related diseases, frailty, senolytics, senolytic therapy
- MeSH terms
- Aging, Animals, Clinical Trials as Topic, DNA Damage, DNA Repair, Humans, Phenotype, Signal Transduction, Cellular Senescence, Inflammation Mediators, Molecular Targeted Therapy
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